New Synthesis of 3-Aminohydantoins via Condensation of Hydra-zines with Isocyanates Derived from  -Amino Esters

A new, simple, and efficient method for the synthesis of 3-aminohydantoins was reported in two steps, starting from the corresponding L -amino esters. Commercially available  -amino esters were converted into the corresponding isocyanate derivatives, which were then subjected to the condensation reaction with hydrazine hydrate and arylhydrazines, in the presence of DMAP and DIPEA. This method provides the corresponding 3-aminohydantoins in moderate and good yields under a simple and practical protocol.

][7][8][9][10] In a recent study, we reported the 3-amino-5-benzylimidazolidine-2,4-dione (3-aminohydantoin derived from phenyl alanine) as a promising scaffold in dopaminergic neuroprotection and neurorescue in the in vivo and in vitro 6-hydroxydopamine models of Parkinson's disease. 11We believe that 3-aminohydantoins are still understudied in medicinal chemistry.This probably arises from the methods of preparation of these compounds, which are not sufficiently developed to make these molecules easily available. 1

Figure 1 Examples of available 3-aminohydantoin-derived drugs
Despite the simplicity of the chemical structure of 3aminohydantoins and their importance as promising scaffolds and bioactive molecules, only few methods describing their synthesis have been reported in the literature.In 1985, Lalezari et al. reported a one-step synthesis of 3-aminohydantoins via the condensation of -aminoacids with tert-butyl hydrazinecarboxylate in the presence of quinoline as the solvent and base.This method requires heating at an elevated temperature (240 °C) during 3-10 h. 12,13Yousong et al. described a seven-step synthesis of substituted 3-aminohydantoin derivatives, starting from an aldehyde and diethylmalonate.The synthesis involves an isocyanate as an intermediate, which is further reacted with an arylhydrazine.An intramolecular cyclization, in the presence of metallic sodium and ethanol affords the corresponding hydantoin. 14Hamuro et al. disclosed a five-step solid-phase synthesis of 3-aminohydantoins from amino acids using Phoxime resin. 15Janda et al. also described a six-step soluble-polymer-supported synthesis of 3-aminohydantoins from amino acids. 16More recently, Beauchemin et al. developed a cascade synthesis of 3-aminohydantoins using amino esters and N-substituted isocyanates. 10These methods have some drawbacks, such as harsh reaction conditions, in some cases low yields, multistep synthesis, and above all the nonavailability of the reagents used in these

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reactions especially for the last three methods. 10,15,16We believe that more economical and practical methods, using more available and less expensive reagents, to easily access 3-aminohydantoins are still needed.
In this work, we developed a new method for the easy access to 3-aminohydantoins using available and inexpensive reagents under relatively mild conditions.This method involves firstly preparing isocyanate derivatives from L- amino esters, and, secondly, reacting these isocyanates with hydrazine hydrate and aromatic hydrazines in the presence of diisopropyl ethylamine (DIPEA, 3 equiv.)and dimethyl aminopyridine (DMAP, 0.2 equiv.) in dimethyl sulfoxide (DMSO) as the solvent to provide 3-aminohydantoin derivatives (Scheme 1).

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Hydantoins 3 and 4 were prepared using different reaction conditions, i.e., temperature and reaction time (Scheme 2).This is probably due to the difference between the reactivity of hydrazine as the nucleophile and that of arylhydrazines.Indeed, it was found that the reaction of isocyanates with hydrazine hydrate requires heating up to 100 °C for 0.5 h to provide the corresponding 3-aminohydantoins 3 with moderate to good yields.However, the reaction of arylhydrazines requires a higher temperature (120 °C) and a longer reaction time (8 h) to provide the corresponding 3-aminohydantoins 4 with satisfactory yields.Notably, only a low yield of the product was obtained when 3amino-5-benzylimidazolidine-2,4-dione was heated at 150 °C without using DMAP. 5In this work, we prepared a series of fourteen 3-aminohydantoins.3-Aminohydantoins 3a-e possessing an NH 2 group linked to N-3 of the heterocycle were isolated in 45-89% yields, whereas substituted hydantoins 4a-i on the N-3 atom of the cycle were obtained in 29-79% isolated yields.While L-amino esters were used as precursors, we found that all synthesized 3-aminohydantoins were obtained in the racemic form.This was confirmed by measuring their optical rotation ([] D = 0 in all cases).This result is somewhat expected, since Beauchemin et al. obtained the same result when they prepared 3-aminohydantoins following their procedure, which required heating to 100 °C. 10 Firstly, the addition of the hydrazine on the isocyanate group leads to the noncyclic intermediate (Scheme 3).Subsequently, by heating the reaction mixture at the appropriate temperature, the cyclization occurred by attack of the nitrogen atom on the ester function.We found that the use of the DIPEA (3 equiv.)/DMAP(0.2 equiv.)system was necessary to ensure product formation.Without using this basic system, significantly lower yields of 3-aminohydantoins were obtained. 5Apparently, the basic system facilitates the transfer of the proton linked to nitrogen which attacks the ester during the cyclization step.In order to confirm the proposed mechanism, we isolated the intermediate formed by the reaction between phenylhydrazine and isocyanate 2a after stirring for 0.5 h at 0 °C and before subjecting the reaction mixture to heating.Both 1 H and 13 C NMR data of the obtained intermediate are in agreement with the proposed structure of the intermediate I highlighted in Scheme 3 (see the Supporting Information).
We believe that our method for the synthesis of 3-aminohydantoins, described in this work, has several advantages over those described in the literature for the following reasons.(i) Nakamura et al. described the synthesis of 3aminohydantoins 3c and 3d as precursors to prepare new useful molecules for the treatment of Alzheimer's desease. 8hese authors used the method of Lalezari et al., 12 which provided the 3-aminohydantoins in 10% and 23%, yields respectively.The same 3-aminohydantoins were prepared using our method under milder conditions and higher yields (3c: 89%, 3d: 45%; Scheme 2).(ii) Janda al. prepared 3-aminohydantoins 3a, 3b, and 3c in six steps starting from the corresponding amino esters. 16The chemical yields obtained using their method are in the 60-67% yield range, whereas our method provided the same 3-aminohydantoins in steps with 46-89% yields (3a: 45%, 3b: 76%, 3c: 89%).(iii) Hamuro et al. 15 reported a five-step procedure to prepare 3-aminohydantoins 4a and 4d in 47% and 34% yields, respectively, starting from the corresponding amino acids.In this work, 3-aminohydantoins 4a and 4d were obtained in two steps with 35% and 79% yields, respectively.(iv) Our method does not require the use of specific reagents, such as Phoxime resin 15 or MeO-PEG-CH 2 CH 2 NH 2 , 16 which are rather expensive polymers used as leaving groups to facilitate the cyclization step.Likewise, aminoisocyanates, used by Beauchemin et al. 10 as reagents to prepare 3-aminohydantoins, are not readily available. 23n summary, we have developed a new method for the synthesis of 3-aminohydantoins in two steps, relying on the use of available and low-cost reagents, such as -amino esters, together with hydrazine hydrate or simple arylhydrazines.This method provides a variety of substituted and nonsubstituted 3-aminohydantoins in moderate to good yields and appears a simpler and more practical method than the previously disclosed ones.This method will allow easier access to 3-aminohydantoins in order to exploit them in the field of medicinal chemistry.Further work taking advantage of this method is under way and will be reported in due course.

Conflict of Interest
The authors declare no conflict of interest.